TGF-beta1 regulates mitochondrial phenotype in hepatocytes of mice in which TGF-beta1 was deleted by targeted disruption. Transfection of cDNA encoding TGF-beta1 reversed the abnormal mitochondrial phenotype, suggesting that lack of TGF-beta1 during embryogenesis is responsible for abnormal mitochondrial biogenesis. The Golgi complex phenotype in TGF-beta1 (-/-) hepatocytes was also abnormal, and likewise reversed to normal following transfection with cDNA encoding TGF-beta1. TGF-beta1 regulates a mitochondrial encoded gene, COX 1, as shown by reduced expression in TGF-beta1 (-/-) livers compared to TGF-beta1 (+/+) livers. Reduction in the level of COX 1 mRNA argues for mitochondriosis being a compensatory mechanism in TGF-beta1 (-/-) livers and hearts. TGF-beta1 (-/-) mice developed mitochondrial cardiomyopathy leading to biventricular dilatation, cardiac failure and death. Ultrastructural analysis demonstrated an abnormal mitochondrial phenotype in both TGF-beta1 (+/-) and TGF-beta1(-/-) mice in cardiac muscle, which has a relatively high basal metabolic rate, whereas in liver, which has a lower metabolic rate, abnormalities are observed only in older TGF-beta1 null mice. Although a specific role of TGF-beta1 in cellular energetics has yet to be demonstrated, these data suggest that it may regulate intracellular thermogenesis and oxydative phsphorylation through mitochondrial biogenesis and function. Surfactant (SP-C) synthesis and the levels of SP-C mRNA transcription were similar in the lungs of TGF-beta1 (-/-) and TGF-beta1(+/+) mice. Surfactant and tubular myelin accumulated in alveolar type II cells of TGF-beta1 (-/-) mice, but not in TGF-beta1(+/+) mice. TGF- beta1 regulates surfactant apoprotein secretion in the lungs acting at the posttranslational level and provides a pathogenetic mechanism for the respiratory distress syndrome in TGF-beta1 (-/-) mice. The accumulation of surfactant in type II cells of TGF-beta1 (-/-) mice supports our hypothesis that TGF-beta1 is a signaling molecule for intracellular vesicular translocation.